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US20140274989A1 - Manufacturing beta-lactam combination products - Google Patents

Manufacturing beta-lactam combination products Download PDF

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Publication number
US20140274989A1
US20140274989A1 US14/212,625 US201414212625A US2014274989A1 US 20140274989 A1 US20140274989 A1 US 20140274989A1 US 201414212625 A US201414212625 A US 201414212625A US 2014274989 A1 US2014274989 A1 US 2014274989A1
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ceftolozane
tazobactam
composition
beta
absence
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Joseph Terracciano
Nicole Miller Damour
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Merck Sharp and Dohme LLC
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Calixa Therapeutics Inc
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Assigned to CUBIST PHARMACEUTICALS, INC. reassignment CUBIST PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DAMOUR, NICOLE MILLER, TERRACCIANO, JOSEPH
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Assigned to CALIXA THERAPEUTICS, INC. reassignment CALIXA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CUBIST PHARMACEUTICALS, INC.
Assigned to MERCK SHARP & DOHME CORP. reassignment MERCK SHARP & DOHME CORP. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CALIXA THERAPEUTICS, INC.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This disclosure relates to processes for the manufacture of pharmaceutical compositions comprising a beta-lactam antibiotic and a beta-lactam inhibitor compound also containing a beta-lactam moiety, including compositions comprising ceftolozane and tazobactam, and resulting pharmaceutical compositions made by these processes.
  • BL-BLI beta-lactamase inhibitor having a chemical structure containing a beta-lactam moiety
  • cephalosporin antibiotic e.g., ceftolozane
  • beta-lactam antibiotics antibiotics having chemical structures containing a beta-lactam moiety
  • Ceftolozane is a cephalosporin antibacterial agent. The antibacterial activity of ceftolozane is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication.
  • PBPs penicillin binding proteins
  • Ceftolozane is also referred to as CXA-101, FR264205, (6R,7R)-3-[(5-amino-4- ⁇ [(2-aminoethyl)carbamoyl]amino ⁇ -1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-( ⁇ (2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl ⁇ amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, or (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(
  • Ceftolozane sulfate (formula (I)) is an example of a pharmaceutically acceptable salt of ceftolozane that can be combined with sodium chloride and other components to obtain an antibiotic composition.
  • Tazobactam is a BLI compound approved for use in combination with piperacillin in an injectable antibacterial product available under commercial names ZOSYN (U.S.) and TAZOCIN (e.g., in Canada, and the United Kingdom).
  • Tazobactam sodium a derivative of the penicillin nucleus, is a penicillanic acid sulfone having the chemical name chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide.
  • the chemical formula is C 10 H 11 N 4 NaO 5 S and the molecular weight is 322.3.
  • the chemical structure of formula (IIa) is tazobactam sodium:
  • CXA-201 comprises ceftolozane and tazobactam in a 2:1 weight ratio formulated for reconstitution prior to parenteral administration.
  • CXA-201 can be provided as a composition comprising ceftolozane sulfate and tazobactam sodium, administered by reconstituting a vial of solid CXA-201 to form a reconstituted injectable formulation.
  • Each vial of CXA-201 contains 1000 mg of ceftolozane active (free base equivalent weight, e.g., provided as a pharmaceutically acceptable salt such as ceftolozane sulfate) and sterile tazobactam sodium at a quantity equivalent of 500 mg of tazobactam free acid, in a solid form.
  • CXA-201 includes other components such as sodium chloride and L-arginine.
  • CXA-201 displays potent antibacterial activity against various gram-negative infections such as, for example, complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or hospital acquired/ventilator-associated bacterial pneumonia (HABP/VABP).
  • Products containing ceftolozane and tazobactam include both a non-penicillin beta-lactam cephalosporin (ceftolozane) and a beta-lactamase inhibitor with a beta-lactam moiety (tazobactam).
  • ceftolozane non-penicillin beta-lactam cephalosporin
  • tazobactam beta-lactamase inhibitor with a beta-lactam moiety
  • compositions containing two or more beta-lactam compounds in accordance with FDA Guidance, as well as pharmaceutical compositions manufactured in compliance with FDA Guidance. Specifically, certain manufacturing methods are provided herein that conform to standards recommended by FDA Guidance for the avoidance of cross-contamination of non-penicillin beta-lactam drugs.
  • a method of manufacturing a composition comprising a non-penicillin beta-lactam antibiotic and a beta-lactam BLI compound in a dedicated production area or in the absence of any compound belonging to a different class of beta-lactam containing compounds.
  • the non-penicillin antibiotic can be a cephalosporin and the beta-lactam BLI compound can be tazobactam.
  • the manufacturing can be carried out in the absence of any compound belonging to other classes of beta-lactam containing compounds, including: penicillins, penems, carbacephems, and monobactams.
  • a composition comprising ceftolozane and tazobactam can be manufactured by a process that includes the step of combining ceftolozane with tazobactam in a dedicated production area or in the absence of any other finished pharmaceuticals or any other pharmaceutical ingredients with chemical structures containing a beta-lactam moiety that would be deemed cross-contaminants under the FDA Guidance.
  • the finished pharmaceutical or active pharmaceutical ingredient can be any non-penicillin beta-lactam of a different class than ceftolozane or tazobactam.
  • Certain methods of manufacturing a composition comprising ceftolozane and tazobactam can include the steps of: (a) receiving the ceftolozane and tazobactam at a dedicated production area; (b) sequential, aseptic filling of the ceftolozane and tazobactam into a container (e.g., a bag or vial); (c) blanketing the container with an inert gas; (d) sealing the container; and (e) inspecting the container prior to secondary packaging.
  • a container e.g., a bag or vial
  • HPLC high performance liquid chromatography
  • the compound of formula (III) was formed in a lyophilized product obtained by lyophilizing a solution comprising both ceftolozane and tazobactam.
  • a pharmaceutical composition can include ceftolozane and tazobactam with less than 1%, 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC or even undetectable amounts of the compound of formula (III) (e.g., less than about 0.03% of the compound of Formula (III) measured by HPLC).
  • compositions can be obtained by a process comprising the steps of (a) lyophilizing ceftolozane in the absence of tazobactam to obtain a lyophilized ceftolozane composition; and (b) combining the lyophilized ceftolozane with tazobactam under conditions suitable to obtain said pharmaceutical composition with the aforementioned purity levels.
  • the combination of the lyophilized ceftolozane composition with tazobactam can include blending the lyophilized ceftolozane composition with lyophilized or crystalline tazobactam material.
  • a pharmaceutical composition comprising a blend of separately lyophilized tazobactam and ceftolozane sulfate in an amount providing 1,000 mg of ceftolozane active per 500 mg of tazobactam active, further comprising less than 0.15%, 0.10%, 0.05% or 0.03% by weight; from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC; or even undetectable amounts (e.g., less than about 0.03% by HPLC) of a compound of formula (III) detectable at a retention time relative to ceftolozane of 1.22 by high performance liquid chromatography (HPLC) using a Develosil column ODS-UG-5; 5 micrometers; 250 ⁇ 4.6 mm, a mobile phase of sodium perchlorate buffer solution (pH 2.5)/CH 3 CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven temperature of 45° C.
  • HPLC high performance liquid chromatography
  • CXA-201 compositions comprising less than about 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC of the compound of formula (III) can be obtained by a process comprising the steps of: (a) forming a first aqueous solution comprising ceftolozane (e.g., in a pharmaceutically acceptable salt such as formula (I)), (b) lyophilizing the first aqueous solution to obtain a lyophilized ceftolozane composition, and (c) blending the lyophilized ceftolozane composition with a tazobactam composition (e.g., tazobactam acid lyophilized in the absence of ceftolozane) in an amount that provides a 2:1 weight ratio between the amount of ceftolozane active and tazobactam active.
  • a tazobactam composition e.g.,
  • the ceftolozane can also be a ceftolozane drug product intermediate.
  • the ceftolozane drug product intermediate further comprises sodium chloride.
  • the ceftolozane drug product intermediate can be prepared by a method comprising: (a) compounding a ceftolozane solution for lyophilization; (b) filtering the solution; (c) lyophilizing the solution into powder; (d) grinding and sieving the powder; and (e) aseptic packaging the powder for delivery to the dedicated production area.
  • provided herein is a method of receiving ceftolozane and tazobactam at a dedicated production area, and combining the ceftolozane with tazobactam in the absence of any finished pharmaceuticals or active pharmaceutical ingredients other than ceftolozane and tazobactam to produce a pharmaceutical composition suitable for administration to a subject.
  • FIG. 1 is a flowchart showing the steps for preparing a CXA-201 composition comprising ceftolozane (referred to as CXA-101) and tazobactam using a blending process, wherein the ceftolozane and tazobactam are lyophilized separately prior to blending as described herein.
  • CXA-101 ceftolozane
  • tazobactam tazobactam
  • FIG. 2 is a flowchart showing the steps for preparing a CXA-201 composition comprising ceftolozane (referred to as CXA-101) and tazobactam using a co-lyophilization process, as described herein.
  • CXA-101 ceftolozane
  • tazobactam tazobactam
  • FIG. 3 is a flowchart showing the blending process for preparing a CXA-201 composition comprising ceftolozane (referred to as CXA-101) and tazobactam in a dedicated production area according to FDA Guidance for the prevention of cross-contamination.
  • CXA-101 ceftolozane
  • tazobactam tazobactam
  • a pharmaceutical composition comprising ceftolozane and tazobactam can be prepared in a dedicated production area in the absence of materials with chemical structures containing a beta-lactam moiety, other than ceftolozane or tazobactam.
  • the pharmaceutical composition is preferably prepared in a dedicated production area for manufacturing antibiotic compounds comprising a non-penicillin beta-lactam compound (e.g., a cephalosporin) and a beta-lactamase inhibitor (BLI) compound with a beta-lactam ring (e.g., tazobactam).
  • a non-penicillin beta-lactam compound e.g., a cephalosporin
  • BBI beta-lactamase inhibitor
  • the facility that manufactures a product containing both cephalosporin and a beta-lactam containing BLI such as tazobactam for sale in the United States is not simultaneously or subsequently used to manufacture or handle any other products within another (non-cephalosporin) Beta-Lactam Class, nor to produce another cephalosporin product without tazobactam (or beta-lactam compound from the same structural class).
  • the phrase “1000 mg ceftolozane” or “1 g ceftolozane” refers to an amount of ceftolozane containing the free base equivalent weight of ceftolozane provided in any suitable salt form.
  • a composition containing 1000 mg of ceftolozane in the ceftolozane sulfate solid form will include greater than 1000 mg of material (e.g., due to at least the additional weight of the sulfate counter ion).
  • a composition containing “1000 mg of ceftolozane” includes an amount of ceftolozane sulfate comprising 1000 mg of the ceftolozane molecule in free base equivalent form.
  • ceftolozane sulfate comprising 1000 mg of the ceftolozane molecule in free base equivalent form.
  • 1147 mg ceftolozane sulfate corresponds to 1000 mg of ceftolozane free base.
  • the phrases “250-750 mg tazobactam,” “250-700 mg tazobactam,” “300-700 mg tazobactam,” “300-650 mg tazobactam,” “350-650 mg tazobactam,” “350-600 mg tazobactam,” “400-600 mg tazobactam,” “400-550 mg tazobactam,” “450-550 mg tazobactam,” or “about 500 mg tazobactam” refer to an amount of tazobactam containing the free acid equivalent weight of tazobactam provided in any suitable salt form.
  • a composition containing 500 mg of tazobactam in the tazobactam sodium solid form will include greater than 500 mg of material (e.g., due to at least the additional weight of the sodium counter ion).
  • 500 mg of material e.g., due to at least the additional weight of the sodium counter ion.
  • 537 mg tazobactam sodium corresponds to 500 mg of tazobactam free acid.
  • a composition containing “500 mg of tazobactam” includes an amount of tazobactam sodium comprising 500 mg of the tazobactam molecule in free acid equivalent form.
  • 125 to 1000 mg sodium chloride per 1000 mg of ceftolozane refers to a ratio of sodium chloride to ceftolozane free base equivalent.
  • 125 to 1000 mg sodium chloride per 1000 mg of ceftolozane includes, for example, 62.5 to 500 mg sodium chloride per 500 mg of ceftolozane, as well as, for example, 25 to 200 mg sodium chloride per 200 mg ceftolozane, etc.
  • Blending refers to a process comprising physically combining ceftolozane and tazobactam, wherein each of ceftolozane and tazobactam have been individually lyophilized (i.e., lyophilized in the absence of one another) prior to blending. Blending refers to mixing the components in a powdered form, which can occur within a unit dosage form container. Blending of ceftolozane and tazobactam is described in Examples 3 and 4, and in FIGS. 1 and 3 .
  • vial means a container for storing pharmaceutical preparations.
  • a single vial may be suitable for holding a single preparation, or may be configured to hold two or more separate preparations simultaneously without mixing.
  • the vial may hold enough preparation for a single dose or multiple doses.
  • the vial may be formed of any suitable material, such as glass or plastic, and various means may be used to seal the vial (e.g., stoppering and crimping).
  • the term “dedicated production area” refers to a manufacturing facility that complies with U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Non - Penicillin Beta - Lactam Drugs: A CGMP Framework for Preventing Cross - Contamination (April 2013) (“FDA Guidance”).
  • the FDA Guidance identifies five beta-lactam antibiotic classes: penicillins, cephalosporins, penems, carbacephems and monobactams (“Beta-Lactam Classes”).
  • a dedicated production area cannot be simultaneously or subsequently used to manufacture or handle another product containing a compound from another Beta-Lactam Class.
  • a “dedicated production area” can include but is not limited to facilities, air handling equipment, and/or process equipment. See section IV.D Containment (4.4) of the ICH Q7 guidance.
  • a beta-lactam BLI refers to any beta-lactamase inhibitor compound with a chemical structure including a beta-lactam moiety (e.g., tazobactam).
  • HPLC measurements reported herein are obtained using a Develosil column ODS-UG-5; 5 micrometers; 250 ⁇ 4.6 mm, a mobile phase of sodium perchlorate buffer solution (pH 2.5)/CH 3 CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven temperature of 45° C.
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a pharmaceutical composition of the present invention to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • a “therapeutically effective amount” of a compound of the invention is meant a sufficient amount of the compound to treat the disorder (e.g., bacterial infection).
  • the specific therapeutically effective amount that is required for the treatment of any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or composition employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see, for example, Goodman and Gilman's, “The Pharmacological Basis of Therapeutics”, Tenth Edition, A.
  • ceftolozane active refers to active portion of a salt form of ceftolozane, i.e., the free base form of ceftolozane.
  • tazobactam active refers to the active portion of a salt form of tazobactam, i.e., tazobactam free acid.
  • references to an amount of a substance as “% of the compound of . . . ” or “% by HPLC” (unless otherwise indicated) refer to the % of a compound detected by high performance liquid chromatography (HPLC) according to the method of Example 9.
  • FDA Guidance refers to the document U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Non - Penicillin Beta - Lactam Drugs: A CGMP Framework for Preventing Cross - Contamination (April 2013) (“FDA Guidance”).
  • the FDA Guidance states that manufacturing facilities dedicated to manufacturing a sensitizing non-penicillin beta-lactam compound should be “completely and comprehensively separated” from areas in the facility in which any class of sensitizing beta-lactam is manufactured. The FDA also considers separation of production facilities for penicillins to be good manufacturing practice.
  • the FDA Guidance can be understood to require the use of a dedicated facility to manufacture antibiotic compounds comprising a non-penicillin beta-lactam compound (e.g., a cephalosporin) and a BLI compound with a beta-lactam ring (e.g., tazobactam).
  • a facility that manufactures a product containing both cephalosporin and a beta-lactam containing BLI such as tazobactam for sale in the United States cannot be subsequently used to manufacture any other products containing beta-lactam ring (e.g., other non-penicillin beta-lactam compounds including other cephalosporin antibiotics cannot be subsequently manufactured in the facility).
  • the FDA Guidance relates to manufacturing and handling beta-lactam antibiotics and other pharmaceutical ingredients having a chemical structure containing a beta-lactam ring.
  • Beta-lactam antibiotics including penicillin and the non-penicillin classes, share a basic chemical structure that includes a three-carbon, one-nitrogen cyclic amine structure known as the beta-lactam ring.
  • the side chain associated with the beta-lactam ring is a variable group attached to the core structure by a peptide bond; the side chain variability contributes to antibacterial activity.
  • the FDA has approved over 34 beta-lactam compounds as active ingredients in drugs for human use.
  • Beta-lactam antibiotics include the following five classes: penicillins (e.g., ampicillin, oxacillin); cephalosporins (e.g., cephalexin, cefaclor); penems (e.g., imipenem, meropenem); carbacephems (e.g., loracarbef); and monobactams (e.g., aztreonam).
  • penicillins e.g., ampicillin, oxacillin
  • cephalosporins e.g., cephalexin, cefaclor
  • penems e.g., imipenem, meropenem
  • carbacephems e.g., loracarbef
  • monobactams e.g., aztreonam
  • Antibiotic pharmaceutical compositions comprising a beta-lactam antibiotic compound (i.e., an antibiotic compound possessing one or more beta-lactam moieties) such as a cephalosporin (e.g., ceftolozane) can be administered with a beta-lactamase inhibitor (BLI) compound.
  • the BLI can be selected to irreversibly inhibit beta-lactamase enzymes responsible for resistance to the beta-lactam antibiotic, thereby increasing susceptibility of bacteria to the antibiotic that would otherwise be resistant in the absence of the BLI.
  • Beta-lactam inhibitor compounds such as clavulanic acid, tazobactam, and sulbactam have weak antibacterial activity but are irreversible inhibitors of many beta-lactamases. Accordingly, BLI compounds can be used in combination with specific beta-lactam antibiotic agents to provide antibacterial compositions with an extended antibacterial spectrum.
  • a manufacturing facility handling a product for sale in the United States containing both a cephalosporin (e.g, ceftolozane) and a penicillin nucleus (e.g., tazobactam) cannot be subsequently used in the manufacture of any other class of beta-lactam products, including all other penicillins, cephalosporins, penems, carbacephems and monobactams or in the manufacture of other finished pharmaceuticals or active pharmaceutical ingredients.
  • non-penicillin beta-lactam drugs can be sensitizing agents and cross-contamination with these types of drugs can initiate the same types of drug-induced hypersensitivity reactions that can be triggered by penicillins, such as life-threatening allergic reactions.
  • Allergic reactions associated with these beta-lactam-type drugs range from rashes to life-threatening anaphylaxis.
  • These allergic reactions are mediated by Immunoglobulin E (IgE) and are a primary concern because they can be associated with significant morbidity and mortality.
  • IgE Immunoglobulin E
  • mice Patients with a history of hypersensitivity to penicillin may also experience IgE-mediated reactions to other beta-lactams, such as cephalosporins (e.g., ceftolozane) (see, e.g., Saxon, A, G N Beall, A S Rohr, and D C Adelman, 1987, Immediate hypersensitivity reactions to beta-lactam antibiotics, Ann Intern Med, 107(2):204-215).
  • cephalosporins e.g., ceftolozane
  • the FDA Guidance can be understood to take the position that non-penicillin beta-lactams (including, e.g., tazobactam) have the potential to sensitize individuals, and subsequent exposure to penicillin may result in severe allergic reactions.
  • the FDA Guidance also states that beta-lactam intermediates and derivatives (precursors to the Active Pharmaceutical Ingredients), including the product prior to purification, can have sensitizing properties or result in antigenic responses that produce allergic reactions.
  • the FDA Guidance states that chemical manufacturing processes associated with non-penicillin beta-lactam drugs should also be designed to reduce the risk of cross-contamination.
  • the FDA Guidance also can be understood to take the position that there is a lack of suitable animal or receptor testing models that are predictive of human sensitivity (see, e.g., Olson, H. et al., 2000, Concordance of the toxicity of pharmaceuticals in humans and in animals, Regul. Toxicol. Pharmacol., 32:56-67), and the threshold dose at which allergenic response could occur is extremely low and difficult to detect with current analytical methods (see, e.g., Pimiento, A. P. et al., 1998, Aztreonam and ceftazidime: evidence of in vivo cross-allergenicity, Allergy, 53:624625 and Shepard, G. M., 1991, Allergy to ⁇ -lactam antibiotics, Immunol. Allergy Clin. North Am., 11(3):611-633).
  • beta-lactam antibiotics are similar to one another in many ways, they may differ in pharmacokinetics, antibacterial activity, and potential to cause serious allergic reactions. Because allergy testing methods have not been well-validated, it is clinically difficult to determine the occurrence and rate of cross-reactivity between beta-lactam antibiotics in humans. (Bernstein, I L, et al., 2008, Allergy diagnostic testing: an updated practice parameter, Ann. Allergy Asthma Immunol., 100:S1-S148). Therefore, undiagnosed or underreported cases of cross-reactivity likely exist.
  • beta-lactam antibiotics have negligible potential for cross-reactivity with beta-lactams of other classes, whereas other beta-lactam compounds may exhibit sensitizing activity as derivatives before the incorporation of side chains that confer antibacterial activity.
  • FDA Guidance although there have been no case reports confirming anaphylactic reactions to a beta-lactamase inhibitor that is also a beta-lactam, these compounds are potentially sensitizing agents, and manufacturers should implement controls to reduce the risk of cross-contamination with beta-lactamase inhibitors as with all other beta-lactam products.
  • the FDA recommends that manufacturers establish appropriate separation and control systems designed to prevent two types of contamination: (1) the contamination of a non-penicillin beta-lactam by any other non-penicillin beta-lactam, and (2) the contamination of any other type of product by a non-penicillin beta-lactam. Accordingly, the FDA recommends that the area in which any class of sensitizing beta-lactam is manufactured be separated from areas in which any other products are manufactured, and have an independent air handling system (“dedicated production area”).
  • Dedicated production areas can include separate facilities, air handling equipment, and/or process equipment (see, e.g., IV.D Containment (4.4) of the ICH Q7 guidance, available at http://www.fda.gov/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/default.htm).
  • This control applies to each of the five classes of sensitizing beta-lactams; the area in which any class of sensitizing beta-lactam is manufactured should be separated from areas in which any other products are manufactured, including any other class of sensitizing beta-lactam.
  • a pharmaceutical composition can be manufactured by combining a ceftolozane composition and a tazobactam composition.
  • the ceftolozane composition comprises ceftolozane prepared and obtained in the absence of tazobactam
  • the tazobactam composition comprises tazobactam prepared and obtained in the absence of ceftolozane.
  • the combination of the ceftolozane composition and the tazobactam composition can be performed within a facility that is compliant with the FDA Guidance (e.g., a facility that is dedicated to the exclusive manufacture of products that include combinations of compounds within the same beta-lactam containing structural classes, such as tazobactam and another cephalosporin).
  • ceftolozane composition in FIG. 1 can be prepared in the absence of tazobactam by forming a first aqueous solution comprising ceftolozane sulfate and other components including excipients, stabilizers, pH adjusting additives (e.g., buffers) and the like.
  • Ceftolozane is a cephalosporin antibacterial agent of formula (Ib).
  • Ceftolozane and/or pharmaceutically acceptable salts thereof are also referred to as CXA-101, FR264205, or by chemical names such as (6R,7R)-3-[(5-amino-4- ⁇ [(2-aminoethyl)carbamoyl]amino ⁇ -1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-( ⁇ (2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl ⁇ amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and 7 ⁇ -[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3- ⁇ 3-amino-4-[3
  • Ceftolozane can be obtained as a pharmaceutically acceptable salt.
  • U.S. Pat. No. 7,129,232 discloses ceftolozane and various ceftolozane salts.
  • a ceftolozane hydrogen sulfate salt is disclosed among ceftolozane salts that can be formed “with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt [e.g., sodium salt, potassium salt, etc.], an alkaline earth metal salt [e.g., calcium salt, magnesium salt, etc.], an ammonium salt; a salt with an organic base, for example, an organic amine salt [e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.]; an inorganic acid addition salt [
  • a ceftolozane composition can also include other components such as (without limitation) sodium chloride, citric acid and L-arginine.
  • sodium chloride results in greater ceftolozane stability (e.g., 125-500 mg sodium chloride per 1,000 mg of ceftolozane active in the ceftolozane composition.
  • L-arginine can be included in the ceftolozane composition to adjust pH of the aqueous solution such that the composition is suitable for injection (e.g., to pH 5-7, including 6-7) prior to lyophilization and to increase the solubility of ceftolozane.
  • the first aqueous solution comprises the composition of Table 11 in the Examples.
  • the ceftolozane can be included in the ceftolozane composition as an amount of ceftolozane sulfate of formula (I) containing a therapeutically effective amount of ceftolozane such as at least about 1,000 mg ceftolozane active (e.g., about 1,147 mg ceftolozane sulfate).
  • the ceftolozane composition comprises 125-500 mg sodium chloride per 1000 mg of ceftolozane active, more preferably about 450-500 mg (including, e.g., 480-500 mg) of sodium chloride per 1,000 mg of ceftolozane active.
  • the composition comprises about 487 mg sodium chloride per 1000 mg of ceftolozane active (e.g., about 1,147 mg of ceftolozane sulfate), and an amount of tazobactam sodium providing the equivalent of about 500 mg of tazobactam active.
  • the ceftolozane composition can be with a tazobactam composition.
  • the tazobactam composition can be prepared in the absence of ceftolozane by forming a second solution comprising tazobactam acid.
  • the compound (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (also known as tazobactam) is a ⁇ -lactamase inhibitor of the following structure:
  • tazobactam can be a free acid, a sodium salt, an arginine salt, or a hydrate or solvate thereof.
  • the tazobactam is tazobactam sodium.
  • the tazobactam sodium powder can be generated by neutralizing tazobactam acid with an alkalizing agent, such as sodium bicarbonate or sodium hydroxide, followed by lyophilization.
  • the tazobactam sodium can be generated by neutralizing tazobactam acid with an alkalizing agent, such as sodium bicarbonate or sodium hydroxide.
  • the tazobactam composition can include a crystalline form of tazobactam, such as tazobactam arginine crystal, for combination with the ceftolozane composition.
  • CXA-201 The pharmaceutical antibiotic composition comprising ceftolozane and tazobactam in a 2:1 weight ratio of ceftolozane active to tazobactam acid (“CXA-201”) displays potent antibacterial activity, including antibiotic activity against infections caused by many Gram-negative pathogens such as Pseudomonas aeruginosa ( P. aeruginosa ), Escherichia coli ( E. coli ), Klebsiella pneumonia ( K. pneumonia ).
  • Pseudomonas aeruginosa P. aeruginosa
  • E. coli Escherichia coli
  • Klebsiella pneumonia K. pneumonia
  • CXA-201 is a pharmaceutical composition useful for intravenous administration for the treatment of complicated intra-abdominal infections and/or complicated urinary tract infections, and is being evaluated for treatment of pneumonia.
  • ceftolozane is combined with the ⁇ -lactamase inhibitor (“BLI”) tazobactam.
  • BLI ⁇ -lactamase inhibitor
  • Tazobactam is a BLI against Class A and some Class C ⁇ -lactamases, with well-established in vitro and in vivo efficacy in combination with active ⁇ -lactam antibiotics.
  • compositions comprising CXA-201 are useful, for example, for the treatment of bacterial infections in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition prepared according to the methods described herein.
  • a method for the treatment of bacterial infections in a mammal can comprise administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising ceftolozane sulfate and sodium chloride.
  • Non-limiting examples of bacterial infections that can be treated by the methods of the invention include infections caused by: aerobic and facultative gram-positive microorganisms (e.g., Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus pneumonia, Streptococcus pyogenes, Viridans group streptococci ), aerobic and facultative gram-negative microorganisms (e.g., Acinetobacter baumanii, Escherichia coli, Haemophilus influenza, Klebsiella pneumonia, Pseudomonas aeruginosa, Citrobacter koseri, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Providencia stuartii
  • bacterial infection is associated with one or more of the following conditions: complicated intra-abdominal infections, complicated urinary tract infections (cUTIs) and pneumonia (e.g., community-acquired, or nosocomial pneumonia).
  • cUTIs complicated intra-abdominal infections
  • pneumonia e.g., community-acquired, or nosocomial pneumonia.
  • Community-acquired pneumonia can include infections caused by piperacillin-resistant, beta-lactamase producing strains of Haemophilus influenza .
  • Nosocomial pneumonia caused by piperacillin-resistant, beta-lactamase producing strains of Staphylococcus aureus and by Acinetobacter baumanii, Haemophilus influenzae, Klebsiella pneumoniae , and Pseudomonas aeruginosa.
  • the manufacturing process for the pharmaceutical compositions can be selected to comply with the FDA Guidance while reducing decomposition of the constituent drug substances and to produce a composition that is stable under a variety of storage conditions.
  • the facility can include separation and control systems, or dedicated production areas, that prevent the contamination of a non-penicillin beta-lactam with another non-penicillin beta-lactam and the contamination of any other product by a non-penicillin beta-lactam.
  • compositions comprising one or more drug substances can be prepared by lyophilization of various solutions containing the drug substance(s). Lyophilization is a process of freeze-drying in which water is sublimed from a frozen solution of one or more solutes. Specific methods of lyophilization are described in Remington's Pharmaceutical Sciences, Chapter 84, page 1565, Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co., Easton, Pa., 1990).
  • compositions comprising ceftolozane and tazobactam can be prepared by a blending process, wherein the ceftozolane and tazobactam are individually lyophilized in the absence of one another, followed by blending the individually lyophilized ceftozolane and tazobactam.
  • compositions comprising ceftolozane and tazobactam prepared by blending (e.g., as described in Example 3) have a different composition compared to compositions prepared by co-lyophilization (e.g., as described in Example 1).
  • ceftolozane and tazobactam individually lyophilized prior to blending led to a pharmaceutical composition comprising a much lower amount of the compound of formula (III):
  • This compound of formula (III) has a relative retention time (RRT) of 1.22 (relative to ceftolozane using the HPLC analysis). This compound is also referred to herein as “the compound RRT 1.22.” Without being bound by theory, the compound RRT 1.22 can be formed by a reaction between ceftolozane and formylacetic acid, a by-product of tazobactam as illustrated in Marunaka et al. (Chem. Pharm. Bull. 1988, Vol. 36 (11), pp. 4478-4487.
  • compositions with controlled amounts of the compound RRT1.22 (formula (III)) (e.g., up to 1% by weight of formula III) can be obtained by blending a first composition comprising a therapeutically effective amount of ceftolozane in the absence of tazobactam with a second composition comprising a therapeutically effective amount of tazobactam in the absence of ceftolozane to form a blended pharmaceutical composition.
  • a first composition comprising a therapeutically effective amount of ceftolozane in the absence of tazobactam
  • a second composition comprising a therapeutically effective amount of tazobactam in the absence of ceftolozane
  • compositions comprising ceftolozane and tazobactam with reduced or even undetectable levels of the compound of formula (III) (e.g., including levels of compound of formula (III) that are not detectable by HPLC according to Example 9 and/or comprise less than 1%, 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC according to Example 9) can be obtained by blending a ceftolozane composition comprising a therapeutically effective amount of ceftolozane in the absence of tazobactam with a tazobactam composition comprising a therapeutically effective amount of tazobactam in the absence of ceftolozane to form a blended pharmaceutical composition.
  • a ceftolozane composition comprising a therapeutically effective amount of ceftolozane in the absence of tazobactam
  • a tazobactam composition comprising
  • compositions can be obtained by a method comprising:
  • ceftolozane aqueous solution
  • an amount of sodium chloride effective to stabilize the ceftolozane e.g., 125-500 mg sodium chloride per 1,000 mg ceftolozane active
  • composition is prepared by a method comprising:
  • an antibiotic pharmaceutical composition is formulated for parenteral administration for the treatment of infections.
  • the composition has a therapeutically effective amount of ceftolozane sulfate and tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of tazobactam active.
  • the pharmaceutical composition is obtained by a process comprising the steps of lyophilizing a first aqueous solution in the absence of tazobactam, wherein the first aqueous solution comprises ceftolozane sulfate, 125 mg to 500 lyophilizing a first aqueous solution in the absence of tazobactam, the first aqueous solution comprising ceftolozane sulfate, to obtain a first lyophilized ceftolozane composition, and blending the lyophilized ceftolozane composition with a tazobactam composition comprising tazobactam prepared and provided in the absence of ceftolozane.
  • the process is performed in the absence of other non-cephalosporin beta-lactam compounds.
  • the pharmaceutical composition comprises an amount of ceftolozane sulfate providing 2,000 mg of ceftolozane active and an amount of tazobactam providing 1,000 mg of tazobactam acid.
  • composition further comprises 125 mg-500 mg of sodium chloride per 1,000 mg of ceftolozane active.
  • the composition of claim 1 manufactured in the absence of any compound belonging to the following classes of beta-lactam containing compounds: penicillins, penems, carbacephems, and monobactams.
  • the tazobactam composition is obtained by lyophilizing a second solution in the absence of ceftolozane, and the second solution comprises tazobactam to form a second lyophilized tazobactam composition.
  • the second solution may comprise tazobactam acid and sodium bicarbonate.
  • the pharmaceutical composition further comprises 125 mg-500 mg of sodium chloride per 1,000 mg of ceftolozane active.
  • the ceftolozane and tazobactam are combined in the absence of any compound belonging to the following classes of beta-lactam containing compounds: penicillins, penems, carbacephems, and monobactams.
  • a the unit dosage form is formulated for parenteral administration for the treatment of complicated intra-abdominal infections or complicated urinary tract infections; and the pharmaceutical composition comprises an amount of ceftolozane sulfate providing 1,000 mg of ceftolozane active and an amount of tazobactam providing 500 mg of tazobactam acid.
  • the pharmaceutical composition in the unit dosage form is formulated for parenteral administration for the treatment of pneumonia; and the pharmaceutical composition comprises an amount of ceftolozane sulfate providing 2,000 mg of ceftolozane active and an amount of tazobactam providing 1,000 mg of tazobactam acid.
  • a method of manufacturing a composition comprising ceftolozane and tazobactam comprises the steps of receiving the ceftolozane and tazobactam at the dedicated production area; filling a vial with a blend of the ceftolozane and tazobactam; and sealing the vial.
  • antibiotic pharmaceutical compositions comprising ceftolozane and tazobactam with less than about 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC of the compound of formula (III) are obtained by a process comprising the steps of: (a) lyophilizing ceftolozane in the absence of tazobactam to obtain a lyophilized ceftolozane composition, and (b) blending the lyophilized ceftolozane composition with a composition comprising tazobactam under conditions suitable for attaining the aforementioned purity levels, e.g., by blending with crystalline tazobactam or lyophilized tazobactam.
  • antibiotic pharmaceutical compositions comprising ceftolozane and tazobactam and less than about 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC of the compound of formula (III) are obtained by a process comprising the steps of: (a) lyophilizing tazobactam in the absence of ceftolozane to obtain a lyophilized tazobactam composition, and (b) blending the lyophilized tazobactam composition with a composition comprising ceftolozane (e.g., lyophilized ceftolozane sulfate).
  • ceftolozane e.g., lyophilized ceftolozane sulfate
  • antibiotic pharmaceutical compositions comprising ceftolozane and tazobactam and less than about 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC of the compound of formula (III) are obtained by a process comprising the steps of: (a) lyophilizing tazobactam in the absence of ceftolozane to obtain a lyophilized tazobactam composition, (b) lyophilizing ceftolozane in the absence of tazobactam to obtain a lyophilized ceftolozane composition, and (c) blending the lyophilized tazobactam composition with the lyophilized ceftolozane composition.
  • compositions can include ceftolozane sulfate and the compound of formula (III).
  • pharmaceutical compositions comprising up to 1% by weight (e.g., 0.13%, 0.15%, 0.30%, 0.38%, 0.74% or 0.97%) of the compound of formula (III) are herein.
  • the pharmaceutical antibiotic compositions can be provided in a unit dosage form (e.g., in a vial).
  • the unit dosage form can be dissolved with a pharmaceutically acceptable carrier, and then intravenously administered.
  • the unit dosage form comprises 1000 mg of ceftolozane active and 500 mg tazobactam, typically 1000 mg ceftolozane active as ceftolozane sulfate and 500 mg of tazobactam active as tazobactam sodium, argininate or free acid.
  • the unit dosage forms are commonly stored in vials.
  • the pharmaceutical composition in a unit dosage form is formulated for parenteral administration for the treatment of pneumonia.
  • Citric acid can be included in an aqueous ceftolozane solution that is lyophilized to obtain the ceftolozane composition in an amount effective to prevent discoloration of the product, due to its ability to chelate metal ions.
  • the citric acid is anhydrous citric acid.
  • the amount of the citric acid is 5-40 mg anhydrous citric acid per 1000 mg of ceftolozane active (including, e.g, 5-35 mg anhydrous citric acid per 1000 mg of ceftolozane, about 21 mg anhydrous citric acid per 1000 mg of ceftolozane and other ranges between 5-40 mg citric acid per 1,000 mg of ceftolozane active).
  • An aqueous ceftolozane solution that is lyophilized to obtain the ceftolozane composition can further comprise L-arginine, in an amount effective to provide a pH of about 5-7, preferably 6-7, alone or in combination with citric acid and/or ceftolozane sulfate.
  • the amount of the L-arginine is 450-750 mg L-arginine per 1000 mg of ceftolozane active, (including intermediate ranges and values, e.g, 450-700 mg L-arginine per 1000 mg of ceftolozane active, 550-600 mg L-arginine per 1000 mg of ceftolozane active, or about 587 mg L-arginine per 1000 mg of ceftolozane active). In one specific embodiment, the amount of the L-arginine is about 600 mg L-arginine per 1000 mg of ceftolozane active.
  • a facility for manufacturing a pharmaceutical composition formulated for parenteral administration for the treatment of complicated intra-abdominal infections or complicated urinary tract infections the pharmaceutical composition comprising ceftolozane sulfate and tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of tazobactam active, the pharmaceutical composition obtained by a process comprising the steps of (a) lyophilizing a first aqueous solution in the absence of tazobactam, the first aqueous solution comprising ceftolozane sulfate, 125 mg to 500 mg of sodium chloride per 1,000 mg of ceftolozane active, to obtain a first lyophilized ceftolozane composition, (b) lyophilizing a second solution comprising tazobactam in the absence of ceftolozane to form a second lyophilized tazobactam composition; and (c) blending the first lyophilized
  • CXA-201 composition comprising tazobactam and ceftolozane by co-lyophilization
  • FIG. 2 The manufacturing process of a CXA-201 composition comprising tazobactam and ceftolozane by co-lyophilization is shown in FIG. 2 .
  • Non-sterile bulk tazobactam and bulk ceftolozane were mixed, followed by dissolution and sterile filtration.
  • the filtrate was then tray-lyophilized to obtain the CXA-201 composition.
  • the CXA-201 composition can be vial-filled as a final drug product.
  • the components of a CXA-201 composition prepared by co-lyophilization are shown in Table 1.
  • Co-Lyophilized Combo Drug Product i.e., a CXA-201 Composition
  • the components of the co-lyophilized CXA-201 composition are shown in Table 2. This composition was prepared, as described above in Example 1.
  • RRT 1.22 was identified as a compound formed by a reaction between ceftolozane and formylacetic acid, which was a by-product of tazobactam as illustrated in Marunaka et al. (Chem. Pharm. Bull. 1988, Vol. 36 (11), pp. 4478-4487).
  • the stability data at 25° C. and at 40° C. have confirmed the continued formation of the compound RRT 1.22 over the course of time.
  • a low energy drum blender that agitates the material by tumbling and also moving the bed up and down is used.
  • a representative process of blending is described as follows, also shown in FIG. 1 .
  • the blender was charged with 23.4 kg of CXA-101 bulk product, and 5.4 kg of tazobactam bulk product. Both the CXA-101 and tazobactam were individually lyophilized beforehand. The material was blended for 180 minutes. In-process tests of content assay for both CXA-101 and tazobactam were performed to assess the homogeneity using the samples of blend materials taken from three places.
  • the relative standard deviation (RSD) for each of CXA-101 and tazobactam content assay was no greater than 2% and the RSD for the ratio of CXA-101/tazobactam was no greater than 2% (See Table 5).
  • a fill and finish process is utilized for the final drug product, which is a pharmaceutical composition comprising CXA-101 and tazobactam at a ratio of 1000 mg/500 mg.
  • Glass vials are washed with WFI and depyrogenated in a Class 100 depyrogenation tunnel at a temperature of 320° C.
  • Pre-washed and pre-siliconized stoppers are autoclaved for 40 minutes at 121° C.
  • the bulk drug product is packaged in a Sterbag® system comprised of three bags.
  • the outer bag is cleaned with disinfectant in a Class 10,000 clean room.
  • the bag system is placed in a pass-through UV box where it is subjected to UV radiation (>20 ⁇ W/cm 2 ) for 20 minutes to sterilize the surface of the outer bag.
  • the outer bag is removed and left in the UV box.
  • the middle bag is placed in a Class A laminar airflow (LAF) hood.
  • LAF laminar airflow
  • the sterile middle bag is removed under LAF.
  • the sterile, bottle-shaped inner bag is then placed in a sterile stainless steel carrier and attached to the filling machine.
  • Sterile bulk CXA-101/tazobactam drug product is filled under a nitrogen blanket into 30-mL, Type I clear glass vials.
  • the sterile drug product is gravity-fed into the filling machine under LAF. Vial fill weights are periodically checked throughout the filling operation to ensure proper operation of the filling line. Filling and stoppering operations are performed under Class 100 LAF conditions. Capping and vial washing are done in the Class 10,000 clean room.
  • the blend drug product was prepared, as described above in Example 3, on lab scale using a small blender.
  • the components of the blend composition are shown in Table 6.
  • Segregation steps to conform with FDA Guidance can include, but are not limited to:
  • ceftolozane composition compounding of ceftolozane substance with excipients such as citric acid, sodium chloride, and L-arginine followed by sterile lyophilization
  • excipients such as citric acid, sodium chloride, and L-arginine followed by sterile lyophilization
  • the ceftolozane/tazobactam drug product is controlled to a pH suitable for making an injectable product, e.g., 5-7, including 6-7, to provide physiological comfort, while still assuring adequate stability for the drug substances.
  • the ceftolozane drug product intermediate is controlled during compounding to pH 6.5 ⁇ 0.5 and is controlled at release to pH 5 to 7.
  • the tazobactam sodium is controlled at release to pH 5 to 7.
  • Ceftolozane/tazobactam following reconstitution with normal saline and dilution for infusion also in normal saline (10 mg/mL ceftolozane; 5 mg/mL tazobactam) is slightly hypertonic, with osmolality approximately 500 mOsm/kg.
  • slightly hypertonic intravenous infusion solutions are not uncommon as drug products are commonly prepared and diluted with already-isotonic solutions, such as normal saline.
  • the generally accepted maximum upper limit for peripheral intravenous administration is approximately 900 mOsm/kg, though admixtures 600 to 900 mOsm/kg are typically administered through a central line. Therefore, to be within the limits of this range, the infusion product is less than 600 mOsm/kg.
  • the excipients in ceftolozane composition were chosen to ensure stability and processability of the ceftolozane drug substance into the drug product.
  • the specific excipients, their quantities and functions are provided in Table 12. All excipients are compendial and typical for sterile pharmaceutical dosage forms, requiring no additional treatment prior to use in the formulation.
  • the excipients are used in levels within the range established in other FDA approved products as described in the Inactive Ingredients Database (IID).
  • HPLC measurements reported herein are obtained using a Develosil column ODS-UG-5; 5 micrometers; 250 ⁇ 4.6 mm, a mobile phase of sodium perchlorate buffer solution (pH 2.5)/CH 3 CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven temperature of 45° C.
  • Sodium Perchlorate Buffer Solution was made by dissolving 14.05 g of sodium perchlorate Monohydrate in 1000.0 mL of water followed by adjusting pH to 2.5 with diluted perchloric acid (1 in 20),
  • Sodium Acetate Buffer Solution pH 5.5 (Diluent) was made by dissolving 1.36 g of sodium acetate trihydrate in 1000.0 mL of water followed by adjusting to pH 5.5 with diluted acetic acid (1 in 10).
  • Sample solution dissolve 20.0 mg, exactly weighed, of Sample, in 20.0 mL of water (Prepare just before injection into HPLC system).
  • System Suitability Solution (1%): take 1.0 mL of the Sample Solution (use first sample if more are present) and transfer into a 100.0 mL volumetric flask, dilute with water to volume and mix.
  • a t area of CXA-101 peak in the sample chromatogram
  • ⁇ A i total peak areas of impurities in the sample chromatogram

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8968753B2 (en) 2013-03-15 2015-03-03 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US9044485B2 (en) 2013-03-15 2015-06-02 Calixa Therapeutics, Inc. Ceftolozane antibiotic compositions
US9724353B2 (en) 2011-09-09 2017-08-08 Merck Sharp & Dohme Corp. Methods for treating intrapulmonary infections
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE112008001301T5 (de) 2007-05-14 2010-04-29 Reserach Foundation Of State University Of New York Induktion einer physiologischen Dispersions-Antwort in Bakterien-Zellen in einem Biofilm
US8906898B1 (en) * 2013-09-27 2014-12-09 Calixa Therapeutics, Inc. Solid forms of ceftolozane
CN104721190B (zh) * 2015-03-26 2017-01-11 新乡医学院 头孢替唑钠注射液及其制备方法
EP3270925B1 (en) * 2016-03-31 2021-11-24 Wockhardt Limited Antibacterial compositions
MX2017013433A (es) * 2016-03-31 2018-01-30 Wockhardt Ltd Composiciones antibacterianas.
US11541105B2 (en) 2018-06-01 2023-01-03 The Research Foundation For The State University Of New York Compositions and methods for disrupting biofilm formation and maintenance
WO2023039947A1 (zh) * 2021-09-18 2023-03-23 湘北威尔曼制药股份有限公司 一种含有头孢哌酮钠和他唑巴坦钠的药物组合物及其应用
US20250107553A1 (en) * 2022-02-01 2025-04-03 Inaba Shokuhin Co., Ltd. Pharmaceutical or food composition for animals

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140187528A1 (en) * 2012-09-27 2014-07-03 Cubist Pharmaceuticals, Inc. Tazobactam arginine antibiotic compositions

Family Cites Families (250)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL37879A (en) 1970-10-27 1974-12-31 Ciba Geigy Ag 3-unsubstituted cephalosporin derivatives,process for their manufacture and compositions containing them
US4299829A (en) 1976-03-12 1981-11-10 Fujisawa Pharmaceutical Co., Ltd. 2-Lower alkyl-7-substituted-2 or 3-cephem 4-carboxylic acid compounds
PH17188A (en) 1977-03-14 1984-06-14 Fujisawa Pharmaceutical Co New cephem and cepham compounds and their pharmaceutical compositions and method of use
US4409217A (en) 1977-03-14 1983-10-11 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4464369A (en) 1977-03-14 1984-08-07 Fujisawa Pharmaceutical Co., Ltd. 7-Acylamino-3-cephem-4-carboxylic acid derivatives and pharmaceutical compositions
US4496562A (en) 1977-03-14 1985-01-29 Fujisawa Pharmaceutical Co., Ltd. 7-Substituted-3-cephem-4-carboxylic acid esters
JPS543087A (en) 1977-06-03 1979-01-11 Fujisawa Pharmaceut Co Ltd Preparation of cephalosporin compound
GB1604738A (en) 1977-07-28 1981-12-16 Yamanouchi Pharma Co Ltd 1,3-dithietane-2-carboxylic acid derivatives and the preparation thereof
JPS609719B2 (ja) 1977-08-06 1985-03-12 武田薬品工業株式会社 セフアロスポリン誘導体およびその製造法
US4370326A (en) 1977-09-13 1983-01-25 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds and composition
IT1192287B (it) 1977-11-14 1988-03-31 Fujisawa Pharmaceutical Co Derivati di acido cefalosporanico ad azione farmaceutica e relativo procedimento di preparazione
US4363807A (en) 1978-04-06 1982-12-14 Fujisawa Pharmaceutical Company, Limited Cepham compounds
SE7804231L (sv) 1978-04-14 1979-10-15 Haessle Ab Magsyrasekretionsmedel
AR228726A1 (es) 1978-05-26 1983-04-15 Glaxo Group Ltd Procedimiento para la preparacion del antibiotico(6r,7r)-7-((z)-2-(2-aminotiazol-4-il)-2-(2-carboxiprop-2-oxiimino)acetamido)-3-(1-piridiniometil)cef-3-em-4-carboxilato
US4264597A (en) 1978-06-06 1981-04-28 Masashi Hashimoto Cephalosporin analogues and processes for the preparation thereof
US4268509A (en) 1978-07-10 1981-05-19 Fujisawa Pharmaceutical Co., Ltd. New cephem compounds and processes for preparation thereof
US4284631A (en) 1978-07-31 1981-08-18 Fujisawa Pharmaceutical Co., Ltd. 7-Substituted cephem compounds and pharmaceutical antibacterial compositions containing them
US4305937A (en) 1978-08-17 1981-12-15 Fujisawa Pharmaceutical Co., Ltd. 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and antibacterial pharmaceutical compositions containing them
US4703046A (en) 1978-09-08 1987-10-27 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds and processes for preparation thereof
EP0009671B1 (en) 1978-09-12 1984-06-13 Fujisawa Pharmaceutical Co., Ltd. Starting compounds for preparing cephem compounds and processes for their preparation
US4327093A (en) 1978-10-24 1982-04-27 Fujisawa Pharmaceutical Co., Ltd. 3,7-Disubstituted-2 or 3-cephem-4-carboxylic acid compounds
DE2945248A1 (de) 1978-11-13 1980-05-22 Fujisawa Pharmaceutical Co Cephem-verbindungen, verfahren zu ihrer herstellung und sie enthaltende antibakterielle pharmazeutische mittel
AU536842B2 (en) 1978-12-29 1984-05-24 Fujisawa Pharmaceutical Co., Ltd. Cephalosporin antibiotics
US4390534A (en) 1978-12-29 1983-06-28 Fujisawa Pharmaceutical Co., Ltd. Cephem and cepham compounds
US4332798A (en) 1978-12-29 1982-06-01 Fujisawa Pharmaceutical Co., Ltd. 7-Amino-thia-diazole oxyimino derivatives of cephem and cephem compounds
US4291031A (en) 1979-02-19 1981-09-22 Fujisawa Pharmaceutical Co., Ltd. 3-Phosphonocephalosporanic acid derivatives, and pharmaceutical composition comprising the same
US4339449A (en) 1979-03-27 1982-07-13 Fujisawa Pharmaceutical Company, Limited Analogous compounds of cephalosporins, and pharmaceutical composition comprising the same
FR2462439A1 (fr) 1979-07-26 1981-02-13 Roussel Uclaf Nouveau procede de preparation de produits derives de l'acide 7-/(2-aryl) 2-hydroxyimino acetamido/cephalosporanique
EP0025199B1 (en) 1979-09-03 1984-10-31 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds, processes for their preparation and pharmaceutical compositions containing them
US4381299A (en) 1980-03-07 1983-04-26 Fujisawa Pharmaceutical Co., Ltd. 7-Amino-thiadiazole oxyimino derivatives of cephem and cepham compounds
US4338313A (en) 1979-10-12 1982-07-06 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4332800A (en) 1979-10-12 1982-06-01 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4409214A (en) 1979-11-19 1983-10-11 Fujisawa Pharmaceutical, Co., Ltd. 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof
US4409215A (en) 1979-11-19 1983-10-11 Fujisawa Pharmaceutical Co., Ltd. 7-Acylamino-3-substituted cephalosporanic acid derivatives and processes for the preparation thereof
US4420477A (en) 1979-11-30 1983-12-13 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4443443A (en) 1979-12-17 1984-04-17 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4405617A (en) 1980-02-11 1983-09-20 Fujisawa Pharmaceutical Co., Ltd. 3-(Propynyltetrazol)thiomethyl-3-cephems
JPS56125392A (en) 1980-03-06 1981-10-01 Fujisawa Pharmaceut Co Ltd Cepham and cephem compound and preparation thereof
US4470980A (en) 1980-03-07 1984-09-11 Interx Research Corp. Method of increasing oral absorption of β-lactam antibiotics
JPS5711909A (en) 1980-06-23 1982-01-21 Shionogi & Co Ltd Stable freeze-dried preparation of beta-lactam
US4369312A (en) 1980-07-04 1983-01-18 Fujisawa Pharmaceutical Co., Ltd. Method of producing oxo-containing azetidinone compounds
US4443444A (en) 1980-08-11 1984-04-17 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
EP0046964B1 (en) 1980-08-29 1986-08-20 Fujisawa Pharmaceutical Co., Ltd. New cephem compounds and processes for preparation thereof
US4416879A (en) 1980-09-08 1983-11-22 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4367228A (en) 1980-10-29 1983-01-04 Fujisawa Pharmaceutical Co., Ltd. Cephem compound and composition
US4431642A (en) 1980-12-01 1984-02-14 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
ES507942A0 (es) 1980-12-15 1983-02-01 Fujisawa Pharmaceutical Co Un procedimiento para preparar derivados del acido 7-acilaminocefalosporanico .
DE3177090D1 (en) 1980-12-31 1989-09-28 Fujisawa Pharmaceutical Co 7-acylaminocephalosporanic acid derivatives and processes for the preparation thereof
US4427677A (en) 1980-12-31 1984-01-24 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
GR76342B (ja) 1981-02-02 1984-08-06 Fujisawa Pharmaceutical Co
US4336253A (en) 1981-03-11 1982-06-22 Eli Lilly And Company Cephalosporin antibiotics
JPS6011917B2 (ja) 1981-04-09 1985-03-28 山之内製薬株式会社 新規なセファロスポリン化合物
DE3118732A1 (de) 1981-05-12 1982-12-02 Hoechst Ag, 6000 Frankfurt Cephalosporinderivate und verfahren zu ihrer herstellung
JPS57193489A (en) 1981-05-21 1982-11-27 Fujisawa Pharmaceut Co Ltd Syn-isomer of 7-substituted-3-cephem-4-carboxylic acid ester and its preparation
GR75487B (ja) 1981-06-22 1984-07-23 Fujisawa Pharmaceutical Co
IE53429B1 (en) 1981-08-03 1988-11-09 Fujisawa Pharmaceutical Co New cephem compounds and processes for preparation thereof
US4436912A (en) 1981-09-08 1984-03-13 Eli Lilly And Company 7-[2-(2-Aminooxazol-4-yl)-2-(oximino)acetamido cephalosporin antibiotics and intermediates therefor
US4430499A (en) 1981-09-08 1984-02-07 Eli Lilly And Company 7-[2-(2-Aminooxazol-4-yl)-2-(oximino)acetamido]cephalosporin antibiotics
US4577014A (en) 1981-09-08 1986-03-18 Eli Lilly And Company Thieno and furopyridinium-substituted cephalosporins
US4521413A (en) 1981-09-14 1985-06-04 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
JPS5859991A (ja) 1981-09-14 1983-04-09 Fujisawa Pharmaceut Co Ltd 新規セフェム化合物
US4450270A (en) 1981-10-02 1984-05-22 Eli Lilly And Company Dioximino cephalosporin antibiotics
US4402955A (en) 1981-10-02 1983-09-06 Eli Lilly And Company Dioximino cephalosporin antibiotics
US4501739A (en) 1982-01-19 1985-02-26 Eli Lilly And Company Thieno and furopyridinium-substituted cephalosporins
DE3207840A1 (de) 1982-03-04 1983-09-15 Hoechst Ag, 6230 Frankfurt "cephalosporinderivate und verfahren zu ihrer herstellung"
JPS58154547A (ja) 1982-03-09 1983-09-14 Nippon Shinyaku Co Ltd アズレン誘導体の安定化法
US4640915A (en) 1982-03-29 1987-02-03 Fujisawa Pharmaceutical Co., Ltd. 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives
AU541028B2 (en) 1982-06-21 1984-12-13 Taiho Pharmaceutical Co., Ltd. 6-unsubstituted penicillin derivatives
JPS58225091A (ja) 1982-06-21 1983-12-27 Taiho Yakuhin Kogyo Kk ペニシリン誘導体及びその製造法
US4563449A (en) 1982-07-19 1986-01-07 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4546101A (en) 1982-09-10 1985-10-08 Fujisawa Pharmaceutical Co., Ltd. New cephem compounds useful for treating infectious diseases in human being and animals and processes for preparation thereof
GB8323034D0 (en) 1983-08-26 1983-09-28 Fujisawo Pharmaceutical Co Ltd 7-substituted-3-vinyl-3-cephem compounds
US4609730A (en) 1982-11-22 1986-09-02 Fujisawa Pharmaceutical Co., Ltd. 7-[substituted imino-2-(2-aminothiazol-4-yl)-acetamido]-3(2,2-dihalovinyl or ethynyl)-3-cephem-4-carboxylic acid (syn isomers), having antimicrobial activities
GR79043B (ja) 1982-12-06 1984-10-02 Fujisawa Pharmaceutical Co
US4608373A (en) 1982-12-13 1986-08-26 Yamanouchi Pharmaceutical Co., Ltd. Cephem compounds
US4463003A (en) 1982-12-22 1984-07-31 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4487768A (en) 1982-12-22 1984-12-11 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
DE3247613A1 (de) 1982-12-23 1984-07-05 Hoechst Ag, 6230 Frankfurt Cephalosporinderivate und verfahren zu ihrer herstellung
US4562073A (en) 1982-12-24 1985-12-31 Taiho Pharmaceutical Company Limited Penicillin derivatives
US4499088A (en) 1983-01-04 1985-02-12 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
DE3316798A1 (de) 1983-05-07 1984-11-08 Hoechst Ag, 6230 Frankfurt Verfahren zur herstellung von cephemverbindungen
FR2550200B1 (fr) 1983-08-01 1988-04-08 Fujisawa Pharmaceutical Co Procede de preparation de composes de cephem a activite antimicrobienne et nouveaux produits ainsi obtenus
JPS6045514A (ja) 1983-08-22 1985-03-12 Shionogi & Co Ltd 安定な抗菌性凍結乾燥製剤
DE3409431A1 (de) 1983-10-08 1985-04-18 Hoechst Ag, 6230 Frankfurt Cephalosporinderivate und verfahren zu ihrer herstellung
EP0137442A3 (de) 1983-10-08 1986-01-15 Hoechst Aktiengesellschaft Cephalosporinderivate und Verfahren zu ihrer Herstellung
US4690921A (en) 1983-10-11 1987-09-01 Yamanouchi Pharmaceutical Co., Ltd. Cephalosporin compounds and salts thereof
EP0138552A3 (en) 1983-10-17 1986-03-19 Eli Lilly And Company Improvements on or relating to 3-bicyclicpyridinium-methyl cephalosporins
US4748172A (en) 1983-10-17 1988-05-31 Eli Lilly And Company 3-bicyclicpyridinium-methyl cephalosporins
US4692443A (en) 1983-10-17 1987-09-08 Eli Lilly And Company 3-bicyclicpyridinium-methyl cephalosporins
GB8329030D0 (en) 1983-10-31 1983-11-30 Fujisawa Pharmaceutical Co Cephem compounds
GB8401093D0 (en) 1984-01-16 1984-02-15 Fujisawa Pharmaceutical Co Cephem compounds
JPS60169486A (ja) 1984-02-10 1985-09-02 Yamanouchi Pharmaceut Co Ltd ７−アミノ−３−置換メチル−３−セフエム−４−カルボン酸およびその低級アルキルシリル誘導体の製造法
GB8406231D0 (en) 1984-03-09 1984-04-11 Fujisawa Pharmaceutical Co Cephem compounds
JPS60214792A (ja) 1984-04-06 1985-10-28 Taiho Yakuhin Kogyo Kk ペナム酸エステル誘導体
US4705851A (en) 1984-09-28 1987-11-10 Fujisawa Pharmaceutical Co., Ltd. Process for the preparation of 3-phosphoniummethyl-3-cephem compounds
US4761410A (en) 1985-01-14 1988-08-02 Fujisawa Pharmaceutical Co., Ltd. Cephem Compounds
NZ214864A (en) 1985-01-21 1988-04-29 Sankei Yakuhin Kk #b#-lactam compounds
GB8504072D0 (en) 1985-02-18 1985-03-20 Fujisawa Pharmaceutical Co Cephem compounds
JPS62103092A (ja) 1985-07-18 1987-05-13 Sagami Chem Res Center β−ラクタム誘導体
JPS6230789A (ja) 1985-08-01 1987-02-09 Yamanouchi Pharmaceut Co Ltd ７−ホルミルアミノセフアロスポリン化合物およびその製造法
US5194432A (en) 1985-11-22 1993-03-16 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
CN86107947A (zh) 1985-11-22 1987-05-27 藤沢药品工业株式会社 新的头孢烯化合物及其制备方法
US4808617A (en) 1985-12-18 1989-02-28 Bristol-Myers Company Lyophilized or precipitated cephalosporin zwitterion and salt combination
JPS62158290A (ja) 1985-12-28 1987-07-14 Banyu Pharmaceut Co Ltd 新規セフアロスポリン誘導体
DE3789466T2 (de) 1986-03-17 1994-07-28 Fujisawa Pharmaceutical Co 3,7-Disubstituierte-3-Cephemverbindungen und Verfahren zu ihrer Herstellung.
JP2690009B2 (ja) * 1986-07-10 1997-12-10 エーザイ 株式会社 セフアロスポリン注射剤
US4833134A (en) 1986-08-19 1989-05-23 Takeda Chemical Industries, Ltd. Cephem compounds
JPS6351388A (ja) 1986-08-22 1988-03-04 Teijin Ltd セフアロスポリン誘導体、その製造法及び抗菌活性組成物
JPS6351389A (ja) 1986-08-22 1988-03-04 Teijin Ltd セフアロスポリン誘導体、その製造法及び抗菌活性組成物
US5162520A (en) 1986-09-22 1992-11-10 Fujisawa Pharmaceutical Co., Ltd. Intermediates for cephem compounds
CA1293719C (en) 1986-09-22 1991-12-31 Takao Takaya Cephem compounds and processes for preparation thereof
US4882434A (en) 1986-10-29 1989-11-21 Takeda Chemical Industries, Ltd. Gamma-lactonecarboxylic acid derivatives and their use as antibacterial agents or intermediates
KR880006244A (ko) 1986-11-24 1988-07-22 후지사와 도모 기찌 로 3-피롤리디닐티오-1-아자바이스클로[3.2.0]햅트2-엔-2-카르복실산 화합물 및 이의 제조방법
DE3784147T2 (de) 1986-11-24 1993-06-03 Fujisawa Pharmaceutical Co 3-pyrrolidinylthio-1-azabicyclo(3.2.0)hept-2-en-2-carbonsaeure-derivate.
AU1630988A (en) 1987-05-30 1988-12-01 Kyoto Pharmaceutical Industries, Ltd. Cephalosporin compound and pharmaceutical composition thereof
IE61679B1 (en) 1987-08-10 1994-11-16 Fujisawa Pharmaceutical Co Water-soluble antibiotic composition and water-soluble salts of new cephem compounds
EP0303172A3 (de) 1987-08-14 1991-05-15 F. Hoffmann-La Roche Ag Oxyimino-Cephalosporine
US5138066A (en) 1987-08-14 1992-08-11 Hoffmann-La Roche, Inc. Intermediates for cephalosporins with sulfur-containing oxyimino side chain
US5073550A (en) 1987-08-14 1991-12-17 Hoffmann-La Roche Inc. Cephalosphorins with sulfur-containing oxyimino side chain
ZA885709B (en) 1987-08-19 1989-04-26 Fujisawa Pharmaceutical Co Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer)
US5663163A (en) 1987-09-07 1997-09-02 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds and processes for preparation thereof
US5210080A (en) 1987-09-07 1993-05-11 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
IE63094B1 (en) 1987-09-14 1995-03-22 Fujisawa Pharmaceutical Co Cephem compound and a process for preparation thereof
DK637888A (da) 1987-11-24 1989-05-25 Hoffmann La Roche Carboxylsyreestere
GB8804058D0 (en) 1988-02-22 1988-03-23 Fujisawa Pharmaceutical Co 3-alkenyl-1-azabicyclo(3 2 0)hept-2-ene-2-carboxylic acid compounds
JP2648750B2 (ja) 1988-03-02 1997-09-03 大塚化学株式会社 β−ラクタム誘導体の製造方法
US5173485A (en) 1988-03-09 1992-12-22 Fujisawa Pharmaceutical Company, Ltd. Cephem compounds
US5336768A (en) 1988-05-24 1994-08-09 Hoffmann-La Roche Inc. Antibacterial cephalosporin compounds
CS273349B2 (en) 1988-03-31 1991-03-12 Hoffmann La Roche Method of cephalosporin's new derivatives production
KR900006811B1 (ko) 1988-05-11 1990-09-21 주식회사 럭 키 신규 세팔로스포린 유도체 및 그의 제조방법
US4963544A (en) 1988-05-23 1990-10-16 Fujisawa Pharmaceutical Company, Ltd. 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds
US5244890A (en) 1988-06-06 1993-09-14 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
EP0997466A1 (en) 1988-10-24 2000-05-03 PROCTER & GAMBLE PHARMACEUTICALS, INC. Novel antimicrobial lactam-quinolones
JP2785195B2 (ja) 1989-01-11 1998-08-13 ソニー株式会社 ディスク装置の光学式エンコーダ
GB8905301D0 (en) 1989-03-08 1989-04-19 Fujisawa Pharmaceutical Co New cephem compound and a process for preparation thereof
US5081116A (en) 1989-04-12 1992-01-14 Yamanouchi Pharmaceutical Co., Ltd. Cephalosporin derivatives
US5102877A (en) 1989-04-28 1992-04-07 Fujisawa Pharmaceutical Co., Ltd. 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds
NO903360L (no) 1989-08-11 1991-02-12 Ici Pharma Antibiotiske forbindelser.
DK0421297T3 (da) 1989-09-30 1994-01-17 Eisai Co Ltd Injicerbare præparater indeholdende cephalosporin som lægemiddel og anvendelse deraf
GB8923844D0 (en) 1989-10-23 1989-12-13 Fujisawa Pharmaceutical Co Carbapenem compounds
US5215982A (en) 1989-11-10 1993-06-01 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
US4982596A (en) 1990-01-26 1991-01-08 Buell Industries, Inc. Die for manufacturing a fastener blank
KR910015587A (ko) 1990-02-27 1991-09-30 후지사와 토모키치로 세펨 화합물
US5234920A (en) 1990-08-23 1993-08-10 Bristol-Myers Squibb Company Antibiotic C-7 catechol-substituted cephalosporin compounds, compositions, and method of use thereof
US5095012A (en) 1990-08-23 1992-03-10 Bristol-Myers Squibb Company Antibiotic c-7 catechol-substituted cephalosporin compounds, compositions, and method of use thereof
US5286721A (en) 1990-10-15 1994-02-15 Fujisawa Pharmaceutical Co., Ltd. 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds
US5281589A (en) 1991-06-15 1994-01-25 Cheil Foods & Chemicals, Inc. 3-fused pyridiniummethyl cephalosporins
US5523400A (en) 1993-04-16 1996-06-04 Hoffmann-La Roche Inc. Cephalosporin antibiotics
KR100194994B1 (ko) 1993-06-05 1999-06-15 손경식 새로운 세펨 화합물
WO1995012601A1 (en) 1993-11-06 1995-05-11 Taiho Pharmaceutical Co., Ltd. Crystalline penicillin derivative, and its production and use
EP0664117A1 (de) 1994-01-25 1995-07-26 F. Hoffmann-La Roche Ag Liposomenlösungen
TW293010B (en) 1994-04-20 1996-12-11 Hui-Po Wang Method for preparing cephalosporin derivatives
US5661144A (en) 1994-08-16 1997-08-26 Meiji Seika Kabushiki Kaisha Cephem derivatives with 3-substituted bis heterocycles
DE4440141A1 (de) 1994-11-10 1996-05-15 Hoechst Ag Neue kristalline Cephem-Säureadditionssalze und Verfahren zu ihrer Herstellung
JPH09110877A (ja) 1995-10-17 1997-04-28 Katayama Seiyakushiyo:Kk セフェム化合物、その製造法及びそれを含有する抗菌剤
KR20000005238A (ko) 1996-04-04 2000-01-25 시오노 요시히코 세펨 화합물 및 그 화합물을 함유하는 약제
AUPN955596A0 (en) 1996-04-30 1996-05-23 Fujisawa Pharmaceutical Co., Ltd. New compound
WO1999028308A1 (en) 1997-11-29 1999-06-10 Truett William L Antibiotics and process for preparation
EP1085846A2 (en) 1998-06-08 2001-03-28 Advanced Medicine, Inc. Multibinding inhibitors of microsomal triglyceride transferase protein
HUP0102350A2 (hu) 1998-06-22 2001-11-28 F.Hoffmann-La Roche Ag. Propenil-cefalosporin-származékok, eljárás előállításukra, ezeket tartalmazó gyógyszerkészítmények, valamint intermedierek
AU5006499A (en) 1998-07-23 2000-02-14 Intrabiotics Pharmaceuticals, Inc. Compositions and methods for the treatment or prevention of pulmonary infections
TW526202B (en) 1998-11-27 2003-04-01 Shionogi & Amp Co Broad spectrum cephem having benzo[4,5-b]pyridium methyl group of antibiotic activity
US6207661B1 (en) 1999-02-22 2001-03-27 Baxter International Inc. Premixed formulation of piperacillin sodium and tazobactam sodium injection
TWI233805B (en) 1999-07-01 2005-06-11 Fujisawa Pharmaceutical Co Stabilized pharmaceutical composition in lyophilized form as antifungal agent
ES2258980T3 (es) 1999-08-16 2006-09-16 Revaax Pharmaceuticals Llc Composiciones farmaceuticas que comprenden acido clavulanico o derivados del mismo para el tratamiento de trastornos del comportamiento.
RU2295342C2 (ru) 2000-04-24 2007-03-20 Дайити Фармасьютикал Ко., Лтд. Стабилизированные жидкие препаративные формы
WO2011101710A1 (en) 2010-02-16 2011-08-25 Wockhardt Research Centre Efflux pump inhibitors
JP3743822B2 (ja) 2000-08-11 2006-02-08 大塚化学ホールディングス株式会社 ペニシリン結晶及びその製造法
JP3743823B2 (ja) 2000-08-11 2006-02-08 大塚化学ホールディングス株式会社 ペニシリン結晶及びその製造法
US6599893B2 (en) 2000-08-29 2003-07-29 Essential Therapeutics, Inc. Cephalosporin antibiotics and prodrugs thereof
JP3306473B1 (ja) 2001-05-01 2002-07-24 大塚化学株式会社 β−ラクタム化合物の無水結晶及びその製造法
PL366507A1 (en) 2001-05-01 2005-02-07 Fujisawa Pharmaceutical Co, Ltd. Cephem compounds
JP2002338578A (ja) 2001-05-14 2002-11-27 Otsuka Chem Co Ltd β−ラクタム化合物の水和物結晶
WO2002102378A1 (en) 2001-06-18 2002-12-27 Revaax Pharmaceuticals, Llc Therapeutic treatment for sexual dysfunction
TWI335332B (en) 2001-10-12 2011-01-01 Theravance Inc Cross-linked vancomycin-cephalosporin antibiotics
US7378408B2 (en) * 2001-11-30 2008-05-27 Pfizer Inc. Methods of treatment and formulations of cephalosporin
AU2003210925A1 (en) 2002-02-07 2003-09-02 Rutgers, The State University Antibiotic polymers
TW200305422A (en) 2002-03-18 2003-11-01 Shionogi & Co Broad spectrum cefem compounds
US6878686B2 (en) 2002-05-24 2005-04-12 Theravance, Inc. Cross-linked glycopeptide-cephalosporin antibiotics
KR100671881B1 (ko) 2002-06-07 2007-01-19 오키드 케미칼즈 앤드 파마수티컬즈 리미티드 세팜 유도체로부터의 페남 유도체 제조방법
US9211259B2 (en) 2002-11-29 2015-12-15 Foamix Pharmaceuticals Ltd. Antibiotic kit and composition and uses thereof
AU2002952355A0 (en) 2002-10-30 2002-11-14 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
ES2290498T7 (es) * 2002-10-30 2015-07-10 Astellas Pharma Inc. Compuestos de cefem
AU2003274518A1 (en) 2002-11-01 2004-05-25 Orchid Chemicals And Pharmaceuticals Ltd A process for the preparation of benzyl 2-oxo-4- (heteroaryl) dithio-alpha-isoprenyl-1- azetidineazetate derivatives
AU2003302472B2 (en) 2002-11-22 2010-10-21 The Johns Hopkins University Target for therapy of cognitive impairment
DE10304403A1 (de) 2003-01-28 2004-08-05 Röhm GmbH & Co. KG Verfahren zur Herstellung einer oralen Arzneiform mit unmittelbarem Zerfall und Wirkstofffreisetzung
JP2004269401A (ja) * 2003-03-07 2004-09-30 Sawai Pharmaceutical Co Ltd 凍結乾燥製剤
AU2003230899A1 (en) 2003-04-14 2004-11-26 Wyeth Holdings Corporation Compositions containing piperacillin and tazobactam useful for injection
RU2322980C2 (ru) 2003-04-14 2008-04-27 Уайт Холдингз Корпорейшн Композиции, содержащие пиперациллин и тазобактам, применимые для инъекции
AU2003902380A0 (en) 2003-05-16 2003-06-05 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
WO2004113350A1 (en) 2003-05-23 2004-12-29 Theravance, Inc. Cross-linked glycopeptide - cephalosporin antibiotics
ATE388153T1 (de) 2003-07-11 2008-03-15 Theravance Inc Quervernetzte glycopeptid-cephalosporin- antibiotika
US7589233B2 (en) 2003-07-29 2009-09-15 Signature R&D Holdings, Llc L-Threonine derivatives of high therapeutic index
US8173840B2 (en) 2003-07-29 2012-05-08 Signature R&D Holdings, Llc Compounds with high therapeutic index
US7273935B2 (en) 2003-08-21 2007-09-25 Orchid Chemicals & Pharmaceuticals, Ltd. Process for the preparation of 3-methylcepham derivatives
KR20060069475A (ko) 2003-09-18 2006-06-21 아스텔라스세이야쿠 가부시키가이샤 세펨 화합물
FR2860235A1 (fr) 2003-09-29 2005-04-01 Yang Ji Chemical Company Ltd Utilisation d'un compose de formule (i) inhibiteur de l'aromatase a des fins therapeutiques et composes de formule (i) en tant que tels
TW200523264A (en) 2003-10-09 2005-07-16 Otsuka Chemical Co Ltd CMPB crystal and method for producing the same
TW200519119A (en) 2003-10-10 2005-06-16 Otsuka Chemical Co Ltd PENAM crystal and process for producing the same
JP4535366B2 (ja) 2003-12-03 2010-09-01 塩野義製薬株式会社 セフェム剤の製造方法
WO2005074925A1 (en) 2004-01-30 2005-08-18 Wyeth Compositions substantially free of galactomannan containing piperacillin and tazobactam
KR20060135796A (ko) 2004-03-05 2006-12-29 시오노기세이야쿠가부시키가이샤 3-피리디늄 메틸세펨 화합물
US7417143B2 (en) 2004-04-07 2008-08-26 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of Tazobactam in pure form
JP2008516967A (ja) 2004-10-14 2008-05-22 ワイス 乳酸ナトリウム希釈液中にピペラシリン、タゾバクタムおよびアミノカルボン酸を含む組成物
US20060099253A1 (en) 2004-10-20 2006-05-11 Wyeth Antibiotic product formulation
US20060173177A1 (en) 2005-01-28 2006-08-03 Gego Csaba L Process for preparation of penam derivatives
CA2597812C (en) * 2005-02-14 2012-01-24 Venus Remedies Limited Parenteral combination therapy for infective conditions with drug resistant bacterium
KR100822519B1 (ko) 2005-02-15 2008-04-16 주식회사종근당 위장 내에서 제어방출되는 단일 매트릭스 정제
AU2006339311A1 (en) 2005-06-07 2007-09-07 Foamix Ltd. Antibiotic kit and composition and uses thereof
ITMI20051630A1 (it) 2005-09-02 2007-03-03 Acs Dobfar Spa Formulazione farmaceutica sterile iniettabile contenente almeno due principi attivi
WO2007041156A2 (en) * 2005-09-29 2007-04-12 Nektar Therapeutics Antibiotic formulations, unit doses, kits, and methods
EP1787641A1 (de) 2005-11-22 2007-05-23 Helm AG Tazobactam-Piperacillin-Lyophilisat
SI1959933T1 (sl) * 2005-12-05 2011-02-28 Sandoz Ag Postopek za pripravo liofiliziranega natrijevega piperacilina v kombinaciji z natrijevim tazobaktamom z izboljšano stabilnostjo po rekonstituciji
WO2007086013A1 (en) 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation comprising of ceftazidime, tazobactam and linezolid
WO2007086014A1 (en) 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation comprising cefpirome, tazobactam and linezolid
WO2007086011A1 (en) * 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation comprising cefepime, tazobactam and linezolid
WO2008075207A2 (en) 2006-04-04 2008-06-26 Foamix Ltd. Anti-infection augmentation foamable compositions and kit and uses thereof
US20090275552A1 (en) 2006-04-28 2009-11-05 Mahesh Vithalbhai Patel Therapy for Treating Resistant Bacterial Infections
US20070286818A1 (en) 2006-06-07 2007-12-13 Wyeth Treating cystic fibrosis with antibiotics via an aerosol drug
WO2007145866A1 (en) 2006-06-07 2007-12-21 Wyeth Treating cystic fibrosis with antibiotics via a swirler delivery
WO2007145868A1 (en) 2006-06-07 2007-12-21 Wyeth Treating cystic fibrosis with antibiotics via an aerosol drug
US20070286817A1 (en) 2006-06-07 2007-12-13 Wyeth Treating cystic fibrosis with antibiotics via a swirler delivery
EP2046802B1 (en) 2006-07-12 2013-08-21 Allecra Therapeutics GmbH 2-substituted methyl penam derivatives
CN101129382B (zh) 2006-08-25 2013-12-25 天津和美生物技术有限公司 含β-内酰胺类抗生素和缓冲组分的抗生素复方
CN101129381B (zh) 2006-08-25 2012-02-01 天津和美生物技术有限公司 含β-内酰胺类抗生素和离子螯合剂的抗生素复方
CN101129383B (zh) 2006-08-25 2014-04-02 天津和美生物技术有限公司 含氨基糖苷类抗生素的抗生素复方
NZ575435A (en) 2006-09-07 2012-01-12 Merial Ltd Soft chewable, tablet, and long-acting injectable veterinary antibiotic formulations
US20080103121A1 (en) * 2006-10-30 2008-05-01 Gole Dilip J Cephalosporin derivative formulation
FI119678B (fi) 2006-11-28 2009-02-13 Ipsat Therapies Oy Beta-laktamaasin käyttö
PL2121593T3 (pl) 2006-12-10 2015-11-30 Chongxi Yu Przezskórne systemy dostarczania antybiotyków beta-laktamowych
DE102007009242A1 (de) 2007-02-22 2008-09-18 Evonik Röhm Gmbh Pellets mit magensaftresistenter Wirkstoff-Matix
WO2008113177A1 (en) 2007-03-20 2008-09-25 Centre De Recherche Sur Les Biotechnologies Marines Compositions comprising polyunsaturated fatty acid monoglycerides or derivatives thereof and uses thereof
ITMI20070568A1 (it) 2007-03-22 2008-09-23 Acs Dobfar Spa Comosizione farmaceutica sterile iniettabile avente piperacillina sodica e tazobactam sodico come principi attivi
US20090098088A1 (en) 2007-10-10 2009-04-16 The Procter & Gamble Company Methods And Kits For The Treatment Of Diverticular Conditions
CA2716514A1 (en) 2008-02-21 2009-08-27 Sequoia Pharmaceuticals, Inc. Hiv protease inhibitor and cytochrome p450 inhibitor combinations
TW200940552A (en) * 2008-03-04 2009-10-01 Elan Pharm Inc Stable liquid formulations of anti-infective agents and adjusted anti-infective agent dosing regimens
ITPI20080025A1 (it) 2008-03-31 2009-10-01 Italmed S R L Composizione ad uso odontoiatrico per il trattamento delle perimplantiti
RU2010143460A (ru) 2008-05-01 2012-06-10 Дзе Проктер Энд Гэмбл Компани (US) Способы и наборы для терапии восстановительных состояний кишечника
CN101265263B (zh) 2008-05-12 2010-06-02 海南百那医药发展有限公司 哌拉西林钠他唑巴坦钠复方注射剂的生产方法
WO2009138847A2 (en) * 2008-05-14 2009-11-19 Orchid Chemicals And Pharmaceuticals Ltd. An improved process for the preparation of cefozopran
WO2010014285A1 (en) 2008-07-30 2010-02-04 Estabrook Pharmaceuticals, Inc. Compositions including clavulanic acid and related methods of use
JP5916129B2 (ja) 2009-06-10 2016-05-11 テックフィールズ バイオケム カンパニー リミテッド 抗菌薬および抗菌薬関連化合物の高透過性組成物またはプロドラッグ
AU2010281439A1 (en) 2009-07-28 2012-03-15 Anacor Pharmaceuticals, Inc. Trisubstituted boron-containing molecules
WO2011112435A1 (en) 2010-03-09 2011-09-15 Merck Sharp & Dohme Corp. FtsZ INHIBITORS AS POTENTIATORS OF BETA-LACTAM ANTIBIOTICS AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCUS
JP2013523830A (ja) 2010-04-06 2013-06-17 プリサイエンス ラブス， エルエルシー ３−ブロモピルバートおよび他のａｔｐ産生の選択的阻害剤を用いる処置の方法
WO2013014497A1 (en) * 2011-07-26 2013-01-31 Wockhardt Limited Pharmaceutical compositions comprising beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor
PT3616695T (pt) * 2011-09-09 2024-11-18 Merck Sharp & Dohme Ceftolozano/tazobactam para tratar infeções intrapulmonares
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US20140274990A1 (en) 2013-03-15 2014-09-18 Cubist Pharmaceuticals, Inc. Ceftolozane pharmaceutical compositions
CN110279698B (zh) * 2013-03-15 2022-10-28 默沙东有限责任公司 头孢特咯瓒抗生素组合物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140187528A1 (en) * 2012-09-27 2014-07-03 Cubist Pharmaceuticals, Inc. Tazobactam arginine antibiotic compositions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Cubist Pharmaceuticals. Business Wire. Cubist Pharmaceuticals Announces Approval of Second Bulk Drug Manufacturing Facility. 2005, available online *
FDA CGMP Guidance. Guidance for Industry: Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for preventing Cross Contamination. FDA. April 2013. 1-10. *
Shanley, Agnes. Pharmaceutical Manufacturing. Facilities of the Future. 2013. . *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9724353B2 (en) 2011-09-09 2017-08-08 Merck Sharp & Dohme Corp. Methods for treating intrapulmonary infections
US10028963B2 (en) 2011-09-09 2018-07-24 Merck Sharp & Dohme Corp. Methods for treating intrapulmonary infections
US8968753B2 (en) 2013-03-15 2015-03-03 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US9044485B2 (en) 2013-03-15 2015-06-02 Calixa Therapeutics, Inc. Ceftolozane antibiotic compositions
US9320740B2 (en) 2013-03-15 2016-04-26 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US9925196B2 (en) 2013-03-15 2018-03-27 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US10420841B2 (en) 2013-03-15 2019-09-24 Merck, Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US11278622B2 (en) 2013-03-15 2022-03-22 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US10933053B2 (en) 2013-09-09 2021-03-02 Merck Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function

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